The present invention is generally in the area of the fabrication of graft copolymers of polyesters and polyamino acids.
Poly(glycolic acid), poly(lactic acid), and their copolymers are synthetic polyesters that have been approved by the FDA for certain uses, and have been used successfully, for example, as sutures and in other biomedical applications such as drug delivery and tissue engineering for treating patients suffering from organ failure or tissue loss. Gilding and Reed, Polymer, 20:1459 (1979); Mooney et al., Cell Transpl., 2:203 (1994); and Lewis, D. H. in Biodegradable Polymers as Drug Delivery Systems, Chasin, M., and Langer, R., Eds., Marcel Dekker, New York, 1990. In tissue engineering applications, isolated cells or cell clusters are attached onto synthetic biodegradable polymer scaffolds in vitro, and then the polymer-cell scaffold is implanted into recipients. Langer and Vacanti, Science, 260:920 (1993). Poly(glycolic acid), poly(lactic acid) and their copolymers have been used as scaffolds to support cell growth, for example of cartilage cells. Freed et al., Bio/Technology, 12:689 (1994). The main advantages of these materials are their degradability in the physiological environment to yield naturally occurring metabolic products, and the ability to control their rate of degradation by varying the ratio of lactic acid to glycolic acid repeat units in the copolymers.
In some tissue engineering applications, certain cells such as hepatocytes do not adhere to these polymers, however, and they cannot be used successfully as supports for cell growth. The cellular response to these polymers including adhesion and growth of cells also cannot be controlled or modified through changes in the polymer structure, because these polymers do not possess functional groups, other than end groups, that permit chemical modification to change their properties, thereby limiting the applications of these polymers.
Barrera et al. described the synthesis of a poly(lactic acid) (pLAL) copolymer consisting of L-lactic acid units and a low concentration of N.epsilon.-carbobenzoxy-L-lysine units. The polymers were chemically modified through reaction of the lysine units to introduce arginine-glycine-aspartic acid containing peptide sequences or growth factors to improve polymer-cell interactions. Barrera et al., J. Am. Chem. Soc., 115:11010 (1993); and U.S. Pat. No. 5,399,665 to Bartera et al. The greatest limitation in the copolymers developed by Barrera et al. is that only a limited number of lysine units can be incorporated into the pLAL backbone. In many tissue engineering applications, the concentration of biologically active molecules attached to the polymer via the lysine groups present in the polymer would be too low to produce the desired interactions between the polymer and the body.
There is a need for the development of optimal materials for use as scaffolds to support cell growth and tissue development in tissue engineering applications. There also is a need for methods for introducing functionalities such as polyamino acids into polyesters in order to improve the biocompatibility and other properties of the polymers. There further is a need for the development of polyester materials which include a sufficient concentration of derivatizable groups to permit the chemical modification of the polymer for different biomedical applications.
It is therefore an object of the invention to provide copolymers of polyesters and polyamino acids which can be chemically modified for different biomedical applications such as tissue engineering applications. It is a further object of the invention to provide graft copolymers of polyesters and polyamino acids with improved properties such as biodegradability and biocompatibility. It is still another object of the invention to provide synthetic polyesters which can be derivatized to include functionalities such as peptide sequences or growth factors to improve the interaction of the polymer with cells.